Accession Number:

ADA624218

Title:

Defects in Histone H3.3 Phosphorylation and ATRX Recruitment to Misaligned Chromosomes during Mitosis Contribute to the Development of Pediatric Glioblastomas

Descriptive Note:

Annual rept. 1 Sep 2014-31 Aug 2015

Corporate Author:

MINNESOTA UNIV MINNEAPOLIS

Personal Author(s):

Report Date:

2015-09-01

Pagination or Media Count:

43.0

Abstract:

Here we identify a conserved feedback mechanism that monitors the relative position of lagging chromosomes during anaphase via the differential phosphorylation of the histone variant H3.3 at Ser31. We examined non-transformed cells induced to missegregate chromosomes by transiently depolymerizing spindle microtubules with cold. After re-warming, correlative same cell live and fixed imaging revealed that isolated chromosomes e.g. lagging in anaphase have hyper-phosphorylated H3.3 Ser31 pS31 along their arms that persists into G1. Surprisingly, during telophase Ser31 phosphorylation along individual chromosomes initiates global phosphorylation of H3.3 Ser31 in both reforming nuclei, suggesting an explanation for why both daughter cells trigger p53 activation in response to a single chromosome missegregation event. pS31 is mimicked by the localization of ATRX to isolated chromosomes. ATRX a member of the SWISNF family of chromatin binding protein. We demonstrate that post-anaphase H3.3 pS31 and ATRX are required to trigger p53 stabilization in the subsequent G1 by microinjection of monospecific antibodies against either pS31 or ATRX into anaphase cells containing lagging chromosomes. This blocks p53 accumulation in G1 nuclei. In summary, we show that p53 cell cycle arrest triggered by chromosome missegregation is mediated via a novel signaling mechanism dependent upon H3.3 S31 phosphorylation and ATRX recruitment to lagging chromosomes. This work provides insight into how aneuploidy is normally monitored and suppressed.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Organic Chemistry

Distribution Statement:

APPROVED FOR PUBLIC RELEASE